Blood is often used in clinic to trace certain constituents to diagnose related diseases. To get blood sample needs a invasive detection requiring arterial or venous puncture, by which means it normally brings a lot of side effects, and needs to be avoided. Therefore, other body fluids are alternative sources to be used for tracing the constituents as being symptomatic of the medical health of patients, including urine, saliva, and tear. It has been more and more interacting to trace the corresponding constituents from tear rather than blood because of its non-invasive test, safety and convenience. However, there are several challenges to measure constituents from tear. First it is hard to collect tear sample. Glass capillaries are normally used to collect test sample [1]. But, it may take at least 10 min to collect 10 μl of tear sample [2]. Secondly, the concentration of the constituents in tear is much lower than that in blood. Table I lists the detectable constituents in tears for the diagnosis of the related disease. This invention is related to continuously detect the glucose and other constituencies in tear through a disposable, nanostructured sensor integrated with contact lens. Below describes the major constituents in tear which can be detected through this invention.
Diabetes mellitus is a chronic systemic disease characterized by disorders in both the metabolism of insulin, carbohydrate, fat and protein and the structure and function of blood vessels [3]. As is known, glucose is the main circulating carbohydrate in the body. In normal individuals, the concentration of glucose in blood is tightly regulated, usually in the range between 80 and 120 mg/100 ml, during the first hour or so following a meal. The hormone insulin, normally produced by the beta cells in the pancreas, promotes glucose transport into skeletal muscle and adipose tissue as well as promoting uptake of glucose by the liver for storage as glycogen [3].
In diabetes mellitus, insulin production and/or uptake is compromised and, consequently, blood glucose can be elevated to abnormal concentrations ranging from 300 to 700 mg/100 ml. Over time, elevated blood glucose can cause serious damage to the body. Diabetes can result in circulatory problems which may lead to kidney failure, heart disease, gangrene and blindness. Diabetes is one of the most significant causes of death in Canada due to diabetic complications and the rapid development of arteriosclerosis in inadequately treated diabetic patients [3].
Accurate determination of glucose levels in body fluids, such as blood, urine, and cerebro-spinal fluid, is a major aid in diagnosing and improving the therapeutic treatment of diabetes. It can reduce the long-term risk for developing coronary artery disease, visual impairment, renal failure, and peripheral vascular disease. The most widespread example of a commercial biosensor is the blood glucose biosensor. A biosensor is a compact analytical device, which converts a biologically induced recognition event into a usable signal [4]. A biosensor includes three (3) parts: (1) the sensitive biological element (biological material, or a biologically derived material or biomimic); (2) the transducer or the detector element) that transforms the signal resulting from the interaction of a target analyte with the biological element into another signal (works in a physicochemical way; optical, piezoelectric, electrochemical, etc.) that can be more easily measured and quantified; (3) the signal processors that is primarily responsible for the display of the results in a user-friendly way.
In hospitals, there is a continual need for medical biosensor based devices that are used for real-time Point-of-Care Testing. Furthermore, recent advances in insulin pump technology have created a demand for concurrent advances in the area of glucose sensing. Currently, commercial blood glucose sensors available for diabetics are chemical sensors based on the enzyme glucose oxidase which breaks down glucose in the presence of oxygen into hydrogen peroxide. The produced hydrogen peroxide reacts either electrically or optically with molecules, producing a change proportional to the amount of glucose within the blood volume.
These biosensors however have the disadvantage of requiring that blood be drawn from the patient through either a forearm or finger prick, such as the Precision Q-I-D and the Glucometer Elite XL. To date, millions of diabetics prick their fingers for a drop of blood a few times a day to check glucose levels. Besides being uncomfortable, these tests can miss sudden dips or spikes in blood sugar. Frequent readings are easier with sensors that can be implanted in a patient's skin. But the glucose sensors available today can cause infections after a few days, and they are bulky and expensive.
In recent years, a few devices have been introduced that allow users to test their glucose levels by drawing blood from their arm instead of the tips of their fingers, such as implantable enzymatic sensors, such as the Medtronic-MiniMed CGMS. This type of device requires an even higher degree of biocompatibility because of the risk of thrombosis or embolism. These cutting edge intravenous sensors exhibit lag times of less than three minutes as well as impressive in vivo stability. However, the major obstacle to the use of enzymatic glucose sensing is a phenomenon known as membrane biofouling, which is the clogging of the selective membrane by other molecules present in the blood stream or interstitial spaces.
Although many methods of measuring blood sugar levels have been investigated [5-11], the inconvenience of blood sugar monitoring has not fundamentally improved in recent years. For this reason, there is clearly a need for the development of non-invasive and continuous method of blood sugar monitoring, which is readily available and simple to perform on a daily basis for a reasonable cost. Generally, continuous glucose level monitoring does not measure blood glucose directly, but relies instead on measurement of the glucose levels in other biological fluids.
Tear fluid is more accessible than blood or interstitial fluid and more continuously obtainable and less susceptible to dilution than urine. The study on the correlation of tear glucose and blood glucose has been reported since 1980's [12]. Diabetic and nondiabetic tear glucose mean values were 0.35±0.04 mmol/L and 0.16±0.03 mmol/L, respectively [13-16].
United States Patents: 20070105176A1 and U.S. Pat. No. 7,166,458 are related to use the implantable artificial lens to monitor the tear/blood glucose level. However, implanted lens device always produce serious side-effect. As other implantable blood glucose sensors, these intravenous sensors require an even higher degree of biocompatibility because of the risk of thrombosis or embolism. Therefore, the present invention is directed to a non-invasive, continuous biosensor (e.g. glucose) which is realized through nanostructure-loaded contact lens. For the case of glucose sensors, the market size has been studied with over $7 billion in 2004. The need in the market is particularly related to the non-invasive and continuous sensors.
The use of glucose sensing contact lenses is a new paradigm in glucose monitoring. The idea of lens sensor devices is to not only correct vision, but to continuously monitor the level of glucose in tears non-invasively as well. A sensing contact lens would sample analytes in the tear fluid located on the surface of the eye. The sensor is preferably relatively inexpensive, mass producible, non-toxic and able to survive sterilization by autoclaving. It has been reported that tear glucose concentrations are related to blood glucose levels [5]. However, insulin concentrations in tears of subjects who were fasted for 12 hours were lower than those in tears of subjects who were fed tear glucose. Thus, it is a challenge to monitor tear glucose at lower concentrations. Furthermore, the current means of detection suffers from the design of the sample collector, suitable bioprocess probing, and the contact lens matrix (contact lens is normally made by hydrogels). To wear contact lens for one week requires that the contact lens needs to be produced with materials with high oxygen permeability.
Various contact lens sensors have been proposed to track tear glucose levels. For instance, WO04046726A2 discloses use of “vesicles” in a surface coating on the contact lenses to entrap the FITC-dextran/TRITC-Con A assay components. TRITC-Con A-FITC has also been disclosed in different patents as an example, such as U.S. Pat. Nos. 6,485,703, and 6,602,702.
However, there are several hurdles to over come to obtain a feasible contact lens sensor, these hurdles relate to the low concentration of tear samples or analyte, non-continuous monitoring, and vision influence. Moreover, most systems proposed use polymer materials (lens materials) as the analyte collector. Unfortunately, these polymer materials are prone to changes in structure depending on pH or temperature. Furthermore, the patents of Novartis AG mention the vesicle, e.g. a nanocapsule having a multilayered shell of polyelectrolytes, which are soft materials, are biodegradable, and lose protein (Con A) in the body. This is a major safety issue.
U.S. Pat. No. 6,681,127 and WO04080297A1 disclose use of a surface coating on contact lenses to entrap glucose assay components.
U.S. Pat. No. 7,329,415 and United States Patent Publication No. 20080063898A1 disclose that a vesicle can include “a nanocapsule having a multilayered shell of polyelectrolytes”. These documents disclose liposome nano-encapsuls in contact lens which are not readily used for glucose monitoring due to the fact they are soft materials which cannot keep a stable shape for long periods of time so that they cannot be used for continuous monitoring.
WO0203855A1 discloses a contact lens where an assay is incorporated “within a discrete zone or spot” or “in a strip on the periphery of the device”.
U.S. Pat. No. 6,485,703 disclose beads to be injected into the skin for glucose monitoring. These beads carry the FITC-dextran/TRITC-Con A assay components. This is not an contact lens device but it is one example of using FITC-dextran/TRITC-Con A to detect glucose.
United States Patent Publication No. 20070105176A1 discloses an implantable system which is a functionalized nanoparticle.
U.S. Pat. No. 7,166,458 discloses an implantable device, utilizing “beads or particles” embedded in a macroporous matrix. United States Patent Publication Nos. 20040241207A1 and 20040096477A1 disclose a contact lens fabricated for drug delivery by nanoencapsulation of a drug within nanocapsules dispersed within the contact lens, so that the drug can diffuse out into the tear film on the eye. Nanocapsules could include silica nanospheres, or gelatin, or sodium alginate nanoparticles.
U.S. Pat. No. 6,589,779 and U.S. Pat. No. 6,602,702 disclose an in vitro system for analyte detection using chemically sensitive particles and FRET signaling. These particles are composed of polymeric resin with fluorescent indicator and quencher chemically coupled to them. The particles are from 0.05-500 microns in diameter.
It would therefore be advantageous to provide a contact lens having incorporated therein a biosensor for monitoring glucose levels in tears.